1. Field of the Invention
This invention relates to methods and compositions, especially those comprising retinoids, preferably topically applied to elderly skin, which are useful for improving keratinocyte and fibroblast proliferation, decreasing matrix metalloproteinase (MMP) expression, and improving collagen synthesis in elderly skin, thus providing as an effect the rejuvenation of aged skin.
2. The State of the Art
As far as mammals go, humans are essentially hairless; that is, most of the skin of the human body can be seen without interference from hair. The skin is thus exposed to whatever insults (natural and man-made) the environment harbors. Since it was first understood that the sun caused erythema, people have taken measures to avoid its “harmful rays.” A century ago, in Elizabethian England, it was the fashion to avoid the sun at all costs. Yet the skin of those Elizabethians still wrinkled and displayed other signs of chronological aging.
Human skin is a complex organ which extends over the entire body. There are different types of skin at different portions of the body; for example, facial skin is different from that of the scalp, and even the skin on the front (palm) of the hand is different than that on the back of the hand. Although the type of skin can vary over a person's body, skin is generally composed of two main layers of tissue. The epidermis or cuticle, the outermost layer, is composed of three superficial and two deep layers. The derma, corium, or cutis vera, the true skin, is composed of a papillary layer above and a reticular layer below.
Since ancient times, a variety of substances have been applied to the skin to improve its appearance, generally by affecting the outermost layer of the skin, or to treat a skin ailment, generally by affecting the true skin. More recently, efforts have been made to rejuvenate the skin and reclaim the elasticity and suppleness lost from exposure to sunlight (UV radiation) and weather.
There is a difference between the physiology of chronologically-aged or intrinsically-aged skin (old skin) in comparison with that of photoaged skin. Old skin typically maintains a smooth and unblemished appearance, in comparison with the leathery, blotchy, and often deep wrinkling of photoaged skin. The epidermis of old skin is typically thinner than normal, whereas that of photoaged aged skin is typically thicker than normal (acanthotic) and atrophies over time. Photoaged skin typically has a large Grenz zone (a wide band of eosinophilic material just beneath the epidermis, and collagen formation and structures indicative of wound healing) which is absent from chronologically-aged skin. See also N. A. Fenske and C. W. Lober, “Structural and functional changes of normal aging skin,” J. Am. Acad. Dermatol., 15:571-585 (1986).
Kligman et al., in EP-A2-0 379,367 describe a method for the treatment or prevention of intrinsically aged skin with retinoids. Kligman et al. tested all trans-retinoic acid (as Retin-A® cream) on albino hairless mice and on 5 elderly Caucasian women; only clinical observations were made of the women before and after the study, and only one biopsy was reported taken and this occurred six months into the treatment (i.e., no reference biopsy was taken from this subject before treatment or from an early period of treatment).
U.S. Pat. Nos. 3,932,665 and 4,934,114 disclose the use of retinal (Vitamin A aldehyde), respectively, for the treatment of acne and for the treatment of skin keratoses; see also U.S. Pat. No. 3,060,229. Retinal and it derivatives have also been found as useful in the treatment of such conditions as wrinkles, warts, psoriasis, eczema, dandruff, and the like (see EP-A2-0 391 033). There are also a number of suggestions that tretinoin can heal or reverse the effects of photoaging. Albert M. Kligman, “Current Status of Topical Tretinoin in the Treatment of Photoaged Skin,” Drugs & Aging, 2(1):7-13 (1992); and Chas. N. Ellis et al., “Tretinoin: Its Use in Repair of Photodamage,” and A. S. Zelickson et al., “Topical Tretinoin in Photoaging: An Ultrastructural Study,” both in Journal of Cutaneous Aging & Cosmetic Dermatology, Vol. 1, No. 1, p. 33-40 and 41-47 (1988).
Burger et al., in U.S. Pat. No. 5,665,367, describes compositions for topical application to the skin that contain naringenin and/or quercetin, and a retinoid. The compositions are described as useful for treating many unrelated skin conditions, such as wrinkles, acne, skin lightening, and age spots. The action of their composition on human skin is described with respect to an enzyme (transglutaminase) important to the formation of the cell envelope and thus to the epidermis. In contrast, the present invention is directed to changes in the dermis and the proliferation of beneficial dermal cells and structures.